Process for the manufacture of delta-androstenol-17-ones-3 containing an unsaturatedside-chain in 17-position and derivatives thereof



Patented July 13, 1943 PROCESS FOR THE MANUFACTURE OF A vANDROSTENOL 17 ONES-3 CONTAINING AN UNSATURATED SIDE-CHAIN IN 17- POSITION AND DERIVATIVES THEREOF Hans Herloff Inhofien, Berlin-Wilmersdorf, Walter-Hohlweg, Hohen-Neuendorf, near Berlin, and Willy Logemann, Berlin-Charlottenbu'rg, Germany, assignors to Schering Corporation, Bloomfield, N. J., a corporation of New Jersey No Drawing. Application November 19, 1938, Serial No. 241,466. In Germany November 27,

This invention relates to a process of producing A -androstenol-l7-ones-3 containing an unsaturated side-chain in l7-position and derivatives thereof.

In Serini, Kiister, and Strassberger U. S. patent applicationlserial No. 145,824, filed June 1, 1937, a process is described of producing unsaturated ketones of the cyclopentanopolyhydrophenanthrene series from the corresponding secondary alcohols, consisting in treating such secondary alcohols in the form of aluminumor magnesium-alcoholates or in the presence of other aluminumor magnesium-alcoholates, with an excess of a ketone or aldehyde to effect an exchange of oxidation stages.

Now we have found that physiologically very valuabl compounds containing in l'l-position an unsaturated side-chain and, in particular, 17- ethenyl or 17-ethinyl-A -androstenol-17-ones-3 can be obtained when 17 ethenyl or 17-ethinyl- A -androstendio1s-3,l7 are used as starting material. One may start with derivatives of the named compounds in which the hydroxyl-group at the carbon atom 17 is substituted by a group adapted to be converted into the hydroxyl-group.

Th ketones or aldehydes required for the process according to the invention are preferably used in excess, the oxidation being the smoother the larger is the excess of ketone or aldehyde; as ketones or aldehydes, we may name, for instance, cyclohexanone, acetone, acetophenone, benzaldeh de.

The keto-compound formed in accordance with the invention can be isolated in pure state from the mixture of reaction in the known manner by fractional crystallisation, distillation or sublimation, and also by means of ketone-reagents, such as semicarbazide and the like.

The following examples serve to illustrate the invention without, however, limiting the same to them.

Example 1 1.8 g. of ethenyl-androstendiol-3,17, prepared in accordance with the process of U. S. patent application Serial No. 111,363, filed by Josef Kathol November 18, 1936, are boiled. with 2 g.

of aluminum isopropylate and a mixture of 100 11cm... (0;. zen-397.4)

C., and a second more soluble fraction with a melting point of 130140 C. The two combined fractions are treated with cold ether, undissolved constituents removed by filtration from the solution, and the clear solution concentrated after the addition of petrol ether until the ethenyl-androstenolone crystallizes out in needles. The separation of higher melting components diflicultly soluble in ether and the crystallization of the soluble component, consisting of ethenyl-androstenolone, by means of petrol ether are repeated several times. The ethenyl-androstenolone is finally obtained in needles melting between 151 and 158 C; (a)n=+67.6. The semicarbazone, prepared by boiling with alcoholic semicarbazide-acetate solution, precipitation with water and recrystallization from dilute acetone, melts at 220-221" C.

Example 2 A solution of 50 g. of l7-ethinyl-androstendiol- 3,17 and 40 g. of aluminum isopropylat in a mixture of 2000 cc. of benzene and 1000 cc. of dry acetone is boiled under reflux for 15 hours at C. bath temperature. Then the reaction mixture is poured into dilute sulfuric acid and, after addition of a large quantity of ether, thoroughly shaken whereby the very difiicultly soluble oxidation product separates in a great measure at the. separating layer. The ethereal solution is washed several times regardless of the material crystallising out whereupon the solution together with the crystal is evaporated to dryness, finally in a vacuum. After two times recrystallisation from chloroform-alcohol whereby the chloroform is evaporated to a large extent and after further filtering 011 by suction and washing with alcohol 31 g. of pure l7-ethinyl-A" -androstenon-S-ol-17 or n -pregneninol-17-one-3, are obtained which melt at 264-266 C. and have a value of rotation of (or) n=+21.5 (in dioxane) Example 3 5 g. of 17eethenyl-androstendiol-3,l7 and 5.4 g. of aluminum isopropylate are heated together with a mixture of 250 cos of toluene and 41 cc. of 4 cyclo-hexanone for one hour to boiling. There- "andin 1427 c; and-a value of rotation of ()n="+'rl.e-

(in dioxane).

Of course, many changes and variations in the reaction conditions and the like may be made in oi the cyclopentano polyhydrophenanthrene series comprising subjecting a member 01 the group consisting of a A androstendiol-3,1'Z having an unsaturated side chain oi two carbon atoms attached to the. 17-carbon and a l'l-derivative thereof in which the hydroxyl groupv is substltuted by a group convertible with the aid of hydrolysis into the hydroxyl group, to the action of a carbonyl-containing compound or the class consisting of aldehydes and ketones in the oresence of a member the group consisting of aluminum secondary alcoholates and magnesium secondaryalcoholates.

-2. A process as set forth in claim 1, wherein the member of the class consisting of aldehydes and ketones is added in excess.

3. Process according to claim 1, wherein the metal secondary alcoholates is an aluminum compound of a saturated aliphatic-monohydric alcohol.

4. Process according to claim 1, wherein the metal alcohoiate is a magnesium alcohoiate of "or; thecyclopentano polyhydrophenanthrene series comprising subjecting a member of the a member 0! the class consisting of lower ali-. phati'c aldehyde and ketones is utilized. 8. Process 01 producing unsaturated ketones group consisting of a A --androstendiol-3,l7 having an unsaturated side chain of two carbon atoms attached to the l'l-carbon and a l'l-de- .rivative thereof in which the hydroxyl group is' substituted bya group convertible with the aid of hydrolysis into the hydroxyl group, to, the action of a carbonyl-containing compound of the class consisting of aldehydes and ketones in the presence or a metal alcoholate oi the starting compound. 4 I

9. Process of producing unsaturated ketones of the cyclopentanopolyhydrophenanthrene series, comprising subjecting a member of the group and ketonesin the presence of aluminum iso-' propylatel 10. Process according to claim 1 wherein the starting compound is d -l'l-ethinyi-andro- 7. A process as set forth in claim 9, wherein stendiol-3, 1'1 j 11. The semicarbazone oi l'l-e l-AP- androstenol-1'I-one-3.

HANS HERLOFF INHOFFEN.

WALTER. HOHLWEG. WILLY LOGElidANN.

. CERTIEFICAfiYE 0F CORRECTIdN. Patent No. 2,525,911. July 15, 1915.

ms HERLOFF INHOFFEN, ET AL.

It is hereby v certified that error appears in the prin'ted specification of the above numbered patent requiring oorrection as follows: Page '2, first column line 56, for "claim 9" read --'c1aim l-; and'second column, line 28, for "0181111 1" read ,-claim 9-; andthet the said Letters Patent should be read withthis correction. therein that the same may conforni to the record of the case in the Patent Office.

Signed and sealed this 51st day of A g A- 945- Henry I Van Arsdale (Sea l) Acting Commissioner of Patents. 

